Session VII
WEIGHING IN ON MICROBIOLOGICAL ADI:
EXPERIENCES AND PERSPECTIVES
Introduction
October 26, 2012
Significance of Human Intestinal Microbiota
• An ever-expanding
understanding of the roles of
human microflora/microbiota
• A search to PubMed with
“Human Intestinal Microbiota”
identified >3000 articles
• Important role of human gut flora
in maintaining human health:
infections, metabolic
diseases, diabetes, obesity,
cancer, etc
Gastroenterology 2008;134(2):577-94
Significance of Human Intestinal Microbiota
nature
2012;486:208
nature
2012;488:178
nature
2012;486:222
Science
2012;336:1268
Science
2012;336:1262
Science
2012;368:120
ADI: a Key Parameter in Regulation of Veterinary Drugs
for Food Animals
• Definition of ADI: a measure of the amount of a specific substance (a
residue of a veterinary drug, food additive, or pesticide) in food or drinking
water that can be ingested (orally) on a daily basis over a lifetime without
an appreciable health risk
• Type of ADI: toxicological (including pharmacological) and
microbiological ADI
• Human food safety assessment of veterinary drugs requires data for
establishment of ADI values
Human Food Safety Assessment of Veterinary Drugs
Toxicity Assessment
Microbiological
Safety Assessment
Metabolism & Residue
Chemistry Assessment
Lab Animal Toxicity Data
No Observed Adverse
Effect Level (NOAEL)
AMR /Effect on
Gut Microflora
Toxicological or
Microbiological ADI
pharmacological ADI
Establishment of
MRLs and WP
Lowest ADI
Microbiological ADI Determination - Chronology
• 1960s: Introduction of ADI concept in EU and JECFA
• 1990s: JECFA’s guidance on the data requirements and the decision tree
approach for mADI determination (1999)
 Determination of the most sensitive adverse effects on the human intestinal
microflora with three concerns:
– Emergence of antimicrobial resistant population
– Disruption of the colonization barrier
– Changes in enzymatic activities (NOEL determination)
• 2000s: Development and Implementation of VICH GL-36 (2004):
Two endpoints and 5 steps
JECFA harmonized with VICH GL-36 (2006)
• 2012: Implementation of revised VICH GL-36 with new guidance on test systems
and assay methodology for assessment of the fraction of oral dose
available to microorganisms in the intestine
Knowledge Gaps and Research Needs?
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Effects of antimicrobials on human gut microflora at therapeutic levels (e.g., antimicrobial
therapy) are well expected and documented. It is more challenging to address effects at the
residual levels (such as those potentially presented in food products) in relation to food safety:
• What are the effects of low-level antimicrobial residues on public health and the
approaches to address them?
Human intestinal flora is a relatively stable group of a huge number of bacterial species. Many
factors (diets, ages, geography, etc) affect intestinal flora compositions among individuals.
• What is “normal” flora?
• How important is it to address the impact of antimicrobial residues in the context
of baseline variations in intestinal flora (in individuals or between individuals)?
Determination of mADI based on one or two endpoints of concern:
• Colonization barrier disruption
• Increase in resistant population
What is more concern for potential risk? Which is more sensitive (i.e. lower ADI)?
In the era of omics (microbiome), new approaches have emerged.
• What are the applications of new methodologies (e.g.,new molecular approaches)
for establishing mADI?
Session Topics
• Safety Evaluation of Antimicrobial Residues in Food
– The microbioogical ADI (Professor P. Silley)
– Impact on Human Intestinal Microbiota – Data (Dr. C.E. Cerniglia)
• Antimicrobial Resistance Surveillance
– Update from NARMS (Dr. P. McDermott)
• Antimicrobial Residues in Food Animals
– Findings and Consequences (Dr. P. Basu)
• Discussion